FUNCTIONS OF BIOGENIC AMINE TRANSPORTERS

描述：(申请人摘要) 生物胺转运体是可卡因、安非他明、 还有抗抑郁药。我的远大目标是理解 这些转运蛋白的功能和机制，特别是它们在 药物成瘾的滥用和治疗药物的作用。一个 导师研究科学家发展奖将让我学习新的 生物胺体内功能研究的必要技术 运输商和获得进一步的经验，然后开始全面 独立研究计划。生物胺转运体已被研究 广泛存在于组织制剂和培养细胞中，间接存在于 整个动物使用化合物来阻断这些转运蛋白。唯一的 对转运蛋白作用的直接评估是最近对 转基因小鼠体内的多巴胺转运蛋白。尽管有重大的新消息 从这项研究中了解到的信息，广泛的适应变化已经设置 这项研究的局限性。因此，我们建议设计一种诱导式 反义抑制系统研究生物胺转运蛋白。在……里面 这种方法，反义RNA将以改进的方式表达 基于四环素操纵子的诱导系统抑制特定的 以可控和可逆的方式传输。我们将评估 该方法首先在培养细胞中的有效性，然后在 转基因小鼠。然后我们将使用这种方法来调查 动物的生理和行为变化。我们希望为您提供新的 关于转运蛋白在整个动物中的功能的信息 它们在药物成瘾中的作用及治疗作用 抗抑郁药。从这些研究中获得的知识最终可能 引导更好的方法来治疗毒瘾、抑郁症和其他 相关疾病。

DESCRIPTION: (Applicant's Abstract) Biogenic amine transporters are the main targets of cocaine, amphetamines, and antidepressants. My broad, long-term objectives are to understand the functions and mechanisms of these transporters, specifically their roles in the addiction to drugs of abuse and the actions of therapeutic drugs. A Mentored Research Scientist Development Award will allow me to learn new techniques necessary to study the in vivo functions of the biogenic amine transporters and to gain further experience before embarking on a fully independent research program. Biogenic amine transporters have been studied extensively in tissue preparations and cultured cells, and indirectly in whole animals using compounds that block these transporters. The only direct assessment of the roles of the transporters is the recent knockout of dopamine transporter in transgenic mice. Despite the significant new information learned from this study, extensive adaptation changes have set limitations to the study. Therefore, we propose to engineer an inducible antisense suppression system to study the biogenic amine transporters. In this approach, an antisense RNA would be expressed with an improved tetracycline operon based inducible system to suppress a specific transporter in a controllable and reversible manner. We will evaluate the effectiveness of the approach in cultured cells first, and next in transgenic mice. Then we will use this approach to investigate the physiologic and behavioral changes of the animals. We hope to provide new information about the functions of the transporters in whole animals and their roles in the addiction to drugs of abuse and the therapeutic actions of antidepressants. The knowledge gained from these studies may eventually lead to better approach to treat drug addictions, depression and other related diseases.